EP3972602A2 - Méthodes de transition vers sélexipag - Google Patents

Méthodes de transition vers sélexipag

Info

Publication number
EP3972602A2
EP3972602A2 EP20727613.0A EP20727613A EP3972602A2 EP 3972602 A2 EP3972602 A2 EP 3972602A2 EP 20727613 A EP20727613 A EP 20727613A EP 3972602 A2 EP3972602 A2 EP 3972602A2
Authority
EP
European Patent Office
Prior art keywords
selexipag
ppa
patient
initiation
oral
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20727613.0A
Other languages
German (de)
English (en)
Inventor
Carol ZHAO
Johanna COLVIN RIESEN
Gary Arnold PALMER
Michael Keating
Brian HARTLINE
Wade BENTON
Camelia DUMITRESCU
Mehul Bipinchandra SHAH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actelion Pharmaceuticals Ltd
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of EP3972602A2 publication Critical patent/EP3972602A2/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to methods for transitioning a patient being treated for pulmonary arterial hypertension to selexipag.
  • Pulmonary arterial hypertension is a form of the broader condition pulmonary hypertension in which a patient has high blood pressure in the lungs.
  • PAH Pulmonary arterial hypertension
  • the increased blood pressure is caused by obstruction in the lung’s small arteries.
  • the cause of PAH is unknown.
  • some causes of PAH include drug use, HIV-infection, connective tissue diseases, autoimmune disorders, to name a few.
  • PAH typically leads to heart damage and, often, death when untreated.
  • the disclosure provides methods of transitioning a patient being treated for pulmonary arterial hypertension with a non-selexipag prostacyclin pathway agent (PPA) to selexipag.
  • the methods include administering selexipag to the patient at a starting dose and increasing to a highest tolerable maintenance dose that is maintained for greater than about 14 days without change or interruption.
  • the patient was taking the non-selexipag PPA for about 30 or more days at the time of selexipag initiation and stopped the non-selexipag PPA less than about 7 days before the selexipag initiation.
  • the patient continued taking the non-selexipag PPA at the time of selexipag initiation and subsequently stopped the non- selexipag PPA.
  • FIG. 1 A is a bar graph showing the change in WHO functional class from baseline to 6 months.
  • FIG. IB is a bar graph showing the change in WHO functional class from baseline to 12 months by route of administration of prior PPA.
  • FIG. 2 is a bar graph showing the change from baseline in median 6- minute walk distance at 6 months and 12 months by route of administration of prior prostacyclin pathway agent.
  • FIG. 3 A is a bar graph showing the change from baseline in assessed risk (improved, maintained, or worsened) at 6 months and 12 months in patients transitioned from inhaled/oral prostacyclin pathway agents.
  • FIG. 3B is a bar graph showing the change from baseline in assessed risk (improved, maintained, or worsened) at 6 months and 12 months in patients transitioned from parenteral prostacyclin pathway agents.
  • the present disclosure provides methods of transitioning a patient being treated for pulmonary arterial hypertension with a non-selexipag prostacyclin pathway agent (PPA) to selexipag.
  • PPA prostacyclin pathway agent
  • the terms“pulmonary arterial hypertension” and“PAH” are interchangeable and define a condition of pulmonary hypertension where the patient has high blood pressure in the lungs. PAH occurs when the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs.
  • the underlying cause of the narrowing is not known, i.e., idiopathic pulmonary hypertension.
  • PAH also is classified into subgroups including (i) familial, or heritable PAH, (ii) PAH caused by drugs or toxins, (iii) PAH associated with other conditions such as connective tissue diseases (scleroderma or lupus), congenital heart problems, high blood pressure in the liver, HIV, infections (schistosomiasis), and sickle cell anemia, (iv) PAH caused by rare blood conditions (pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis, or (v) PAH in babies (persistent pulmonary hypertension of the newborn).
  • familial or heritable PAH
  • PAH caused by drugs or toxins
  • PAH associated with other conditions such as connective tissue diseases (scleroderma or lupus), congenital heart problems, high blood pressure in the liver, HIV, infections (schistosomiasis), and sickle cell anemia
  • PAH caused by rare blood conditions pulmonary veno-occlusive disease or pulmonary capillary
  • the methods described herein also may include a determination that the patient has PAH. Typically, that determination is made by an attending physician. A diagnosis or determination of PAH may be performed using techniques known by those of skill in the art. For example, a right-heart catheterization may be conducted to confirm pulmonary arterial hypertension in a patient.
  • the methods described herein advantageously improve the patient’s World Health Organization functional class after about 12 months following selexipag initiation. In other embodiments, the methods improve the patient’s 6- minute walk distance after about 12 months following selexipag initiation. In further embodiments, the methods described herein advantageously improve the patient’s World Health Organization functional class and 6-minute walk distance after about 12 months, following selexipag initiation.
  • the patient Prior to initiating treatment with selexipag, the patient is typically in World Health Organization (WHO) functional class II, III, or IV.
  • WHO World Health Organization
  • the WHO class ifies pulmonary hypertension into classes I-IV. See, Table A.
  • the patient is in WHO functional class II prior to treatment with selexipag.
  • the patient is in a WHO functional class III prior to treatment with selexipag.
  • the patient is in WHO functional class
  • the patient Prior to initiating treatment with selexipag, the patient will have been taking the non-selexipag PPA. In some embodiments, the patient will have been taking the non-selexipag PPA for about 30 days or more at the time of selexipag initiation. In other embodiments, the patient will have been taking the non-selexipag for at least about 30 days, about 60 days, about 90 days, about 180 days, about 210 days, about 240 days, about 270 days, about 300 days, about 330 days, about 360 days, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years.
  • the patient will have stopped taking the non-selexipag PPA upon initiating treatment with selexipag. In some embodiments, the patient will have stopped taking the non-selexipag less than about 7 days before the selexipag initiation. In other embodiments, the patient continued taking the non-selexipag PPA at the time of selexipag initiation and subsequently stopped the non-selexipag PPA. Thus, there may be some overlap in the dosing of selexipag and the non-selexipag PPA.
  • non-selexipag prostacyclin pathway agent or“non-selexipag PPA” as used herein refers to any pharmaceutical agent that acts as a prostatcyclin pathway agent, but is not selexipag or its metabolite, as defined herein.
  • the non-selexipag PPA may be an inhaled PPA, an oral PPA, or a parenteral PPA.
  • the non-selexipag PPA is an inhaled or oral PPA.
  • the non-selexipag PPA is an inhaled PPA.
  • the non-selexipag PPA is an oral PPA.
  • the non-selexipag PPA is a parenteral PPA such as a
  • non-selexipag parenteral PPA is a subcutaneous PPA. In other aspects, the non-selexipag parenteral PPA is an intravenous PPA.
  • Non-limiting examples of non-selexipag PPAs include epoprostenol (Flolan®, Veletri®), treprostinil (Remodulin®, Tyvaso®, Orenitram®), or iloprost (IlomedinTM, Ventavis®).
  • the non-selexipag PPA is intravenous epoprostenol, treprostinil, or iloprost.
  • the non-selexipag PPA is subcutaneous treprostinil. In further embodiments, the non-selexipag PPA is inhaled treprotinil or iloprost. In still other embodiments, the non-selexipag PPA is oral treprostinil.
  • the methods comprise administering a starting dose of selexipag to the patient and increasing it to a highest tolerable maintenance dose that is maintained for greater than about 14 days without change or interruption.
  • the selexipag is administered at a starting dose and is increased to determine a maintenance dose.
  • the term“maintenance dose” as used herein refers to the amount of selexipag that may be administered to a patient per day, without resulting in adverse physical and/or pharmacological effects. Thus, the maintenance dose is typically evaluated for each patient on an individual basis.
  • the starting dose of selexipag is the same as the maintenance dose. In further aspects, the starting dose of selexipag is lower than the maintenance dose.
  • the starting dose or the maintenance dose, on a daily basis is at least about 10 pg.
  • the starting dose or the maintenance dose, on a daily basis is at least about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, about 2500, about 2600, about 2700, about 2800, about 2900, about 3000, about 3100, about 3200, about 3300, about 3400, or about 3500 pg.
  • the starting dose is about 200 pg, twice daily.
  • the daily dose may be administered once daily, twice daily, or thrice daily, preferably twice daily.
  • the maintenance dose not exceed about 1600 pg twice daily, i.e., 3200 pg per day.
  • the maintenance dose, twice daily is about 100 to about 3500 pg, about 200 to about 3200, about 200 to about 3000, about 200 to about 2800, about 200 to about 2600, about 200 to about 2400, about 200 to about 2200, about 200 to about 2000, about 200 to about 1800, about 200 to about 1600, about 200 to about 1400, about 200 to about 1200, about 200 to about 1000, about 200 to about 800, about 200 to about 600, about 200 to about 400, about 400 to about 3200, about 400 to about 3000, about 400 to about 2800, about 400 to about 2600, about 400 to about 2400, about 400 to about 2200, about 400 to about 2000, about 400 to about 1800, about 400 to about 1600, about 400 to about 1400, about 400 to about 1200, about 400 to about 1000, about 400 to about 800, about 400 to about 600, about 600 to about 3200,
  • the maintenance dose, on a twice daily basis is about 200 to about 1600 pg. In other embodiments, the maintenance dose is about 1000 pg to about 1600 pg twice daily. In yet further embodiments, the maintenance dose, on a twice daily basis, is about 1400 to about 1600 pg.
  • the starting dose is increased until the maintenance dose is reached.
  • This period of increasing the dose may be determined by one skilled in the art.
  • the time to reach the maintenance dose is at least about 1 week. In some embodiments, the time to reach the maintenance dose is at least about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, or about 16 weeks.
  • the time to reach the maintenance dose is about 2 to about 16 weeks, about 2 to about 14 weeks, about 2 to about 12 weeks, about 2 to about 10, weeks, about 2 to about 8 weeks, about 2 to about 6 weeks, about 2 to about 4 weeks, about 4 to about 16 weeks, about 4 to about 14 weeks, about 4 to about 12 weeks, about 4 to about 10 weeks, about 4 to about 8 weeks, about 4 to about 6 weeks, about 5 to about 15 weeks, about 5 to about 10 weeks, about 6 to about 16 weeks, about 6 to about 14 weeks, about 6 to about 12 weeks, about 6 to about 10 weeks, about 6 to about 8 weeks, about 8 to about 16 weeks, about 8 to about 14 weeks, about 8 to about 12 weeks, about 8 to about 10 weeks, about 10 to about 16 weeks, about 12 to about 16 weeks, about 12 to about 14 weeks, or about 14 weeks to about 16 weeks.
  • the time to reach the maintenance dose is about 5 to about 10 weeks.
  • the selexipag dose is increased as determined by one skilled in the art until the maintenance dose is determined. In some embodiments, the selexipag dose is increased daily. In other embodiments, the selexipag dose is increased weekly. In further embodiments, the selexipag dose is increased monthly. Preferably, the selexipag dose is increased weekly (based on a 7-day week). When increased weekly, the selexipag dose may be administered on the same day each week or within 1 day within the scheduled dosing day.
  • the next dose of selexipag may be administered on Sunday, Monday, or Tuesday of the following week.
  • the selexipag dose may be administered of the same day each month or within 3 days of the next scheduled dosing day.
  • the next dose of selexipag may be administered on February 4 th , 5 th , 6 th , 7 th , 8 th , 9 th , or 10 th .
  • the maintenance dose is maintained during a maintenance phase.
  • the length of this maintenance phase may be determined by one skilled in the art and is, typically, at least about 14 weeks, and may continue as long as the patient is in need of therapy.
  • the maintenance phase is about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, about 30, about 32, about 34, about 36, about 38, about 40, about 42, about 44, about 46, about 48, about 50, or about 52 weeks.
  • the maintenance phase is at least about 14 weeks. In further embodiments, the maintenance phase is at least about 26 weeks.
  • Additional dose increases may occur following the maintenance phase as determined by those skilled in the art. However, any such increases desirably do not exceed 1600 pg twice daily.
  • the methods include administering a therapeutically effective amount of the selexipag.
  • therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a human that is being sought by a researcher, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the selexipag may be administered once daily, twice daily, or thrice daily to achieve the therapeutically effective amount. In some aspects, the selexipag is administered once daily. In other aspects, the selexipag is administered twice daily. In further aspects, the selexipag is administered thrice daily. Preferably, the selexipag is administered twice daily to achieve the therapeutically effective amount.
  • the term“selexipag” refers to 2- (4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ -N- (methanesulfonyl)acetamide of formula (I).
  • “selexipag” also refers to amorphous or crystalline forms of selexipag, such as polymorphs thereof.
  • the selexipag is a crystalline form, such as a polymorph.
  • the selexipag is an amorphous form.
  • the selexipag is the Form I as described in U.S. Patent Nos. 8,791,122 and 9,284,280, Form II as described in U.S. Patent No. 9,340,516, or Form III as described in U.S. Patent No. 9,440,931, all of which are incorporated by reference herein.
  • the crystallinity may be determined by those skilled in the art using one or more techniques such as, e.g ., single crystal x-ray diffraction, powder x-ray diffraction, differential scanning calorimetry, melting point, among others.
  • “Selexipag” as used herein includes anhydrous or hydrates thereof. In certain embodiments, the selexipag is an anhydrous form. In other embodiments, the selexipag is a hydrate thereof.
  • “Selexipag” as used herein further refers to solvates thereof. Such solvates include a molecule of a solvent bound through intermolecular forces or chemical bonds to one or more locations of the selexipag molecule.
  • the term“selexipag” may also include pharmaceutically acceptable salts thereof, which may readily be selected by those skilled in the art.
  • A“pharmaceutically acceptable salt” is intended to mean a salt of selexipag that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, e.g. , Berge,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66: 1-19, and Handbook of
  • Selexipag can be used in the form of a free base or acid, but can also be used after forming into a pharmaceutically acceptable salt by a known method.
  • examples of“salt” include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid, and salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid.
  • examples of“salt” include alkali metal salts such as sodium salt and potassium salt, and alkali earth metal salts such as calcium salt.
  • Geometrical isomers (Z form and E form) of selexipag or mixtures thereof are also contemplated.
  • Selexipag is commercially available as understood to those skilled in the art. See, e.g., U.S. Patent No. 7,205,302, which is incorporated by reference herein.
  • selexipag is available as Uptravi® and also is known as ACT-293987 or NS-304.
  • Selexipag is an agonist of the prostacyclin receptor and may be prepared according to the process as disclosed in U.S. Patent No. 7,205,302.
  • the present disclosure also contemplates the administration of selexipag metabolites.
  • the selexipag metabolite is metabolically active compound.
  • the selexipag metabolite is of formula Ml. Ml is also known under the code name ACT-333679 or MRE-269.
  • the terms“treating”,“treatment” and the like shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder.
  • the terms“treating” and“treatment” also include the administration of the compounds or pharmaceutical compositions as described herein to (a) alleviate one or more symptoms or complications of the disease, condition or disorder; (b) prevent the onset of one or more symptoms or complications of the disease, condition or disorder; and/or (c) eliminate one or more symptoms or complications of the disease, condition, or disorder.
  • the terms“preventing”, “prevention” and the like shall include (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delaying, slowing or avoiding of the development of additional symptoms; and/or (d) slowing, or avoiding the development of the disorder or condition to a later stage or more serious form.
  • a patient in need thereof shall include any patient or patient who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Further, a patient in need thereof may additionally be a patient who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition.
  • the patient may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the patient's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.
  • the terms“subject” and“patient” are interchangeably used herein to refer to a human, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the therapeutically effective amount of selexipag is safe.
  • safe shall mean without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • compositions containing selexipag as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • composition and“formulation” are used interchangeably and encompass a product comprising the specified ingredients in the specified amounts, as well as any product, such as a pharmaceutical product, which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • a summary of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • Selexipag may be administered to a patient neat or in a mixture with a pharmaceutically acceptable non-toxic inert carrier, for example, as a pharmaceutical composition containing the compound at a level of 0.1% to 99.5wt%, preferably 0.5% to 90%, based on the total weight of the composition.
  • a pharmaceutical composition containing the compound at a level of 0.1% to 99.5wt%, preferably 0.5% to 90%, based on the total weight of the composition.
  • auxiliary agents for formulations such as solid, semi-solid and liquid diluent, filler and other auxiliary agents for drug formulations may be used. It is desirable that a pharmaceutical composition is administered as a unit dosage form.
  • the pharmaceutical composition can be administered into tissue, or intravenously, orally, topically (percutaneously) or rectally. It is a matter of course that a dosage form suitable for any of the administration modes described above is employed. For example, oral administration is preferable.
  • the pharmaceutical compositions may be administered by a number of routes as determined by those skilled in the art.
  • the pharmaceutical compositions are administered by route that is suitable for selexipag.
  • the pharmaceutical compositions are administered orally, parenterally, or any combination thereof. In other embodiments, the pharmaceutical compositions are administered orally. In further embodiments, the pharmaceutical compositions are administered parenterally.
  • the pharmaceutical compositions may administered in a form suitable for the selected route of administration.
  • the pharmaceutical compositions may be administered as suspensions, elixirs, solutions, powders, pills such as capsules, tablets, or caplets, pastilles, granules, syrups, thin films, lozenges, sprays, pastes, or injections.
  • the pharmaceutical compositions are administered as injections such as intradermal injections, subcutaneous injections, intramuscular injections, intraosseous injections, intraperitoneal injections, or intravenous injections.
  • the pharmaceutical compositions are administered as suspensions, elixirs, solutions, powders, pills such as capsules (hard or soft), tablets, or caplets, pastilles, granules, syrups, thin films, lozenges, sprays, or pastes.
  • the pharmaceutical compositions are administered as suspensions, elixirs, solutions, powders, pills such as capsules (hard or soft), tablets, or caplets, pastilles, granules, syrups, thin films, lozenges, sprays, or pastes.
  • the pharmaceutical compositions are administered as suspensions, elixirs, solutions, powders, pills such as capsules (hard or soft), tablets, or caplets, pastilles, granules, syrups, thin films, lozenges, sprays, or pastes.
  • the pharmaceutical compositions are administered as suspensions, elixirs, solutions, powders, pills such as capsules (hard or soft), tablets, or caplets, pastilles, granules, syrups, thin films, lozenges
  • compositions are administered via a continuous infusion via a central venous catheter, using, e.g., an ambulatory pump or implantable pump.
  • the pharmaceutical compositions are administered via continuous infusion using a
  • the pills may be formulated for swallowing, chewable, sublingual use, or buccal use, or may be effervescent to be dissolved or dispersed in water prior to
  • the pharmaceutical product comprises a pill, tablet, powder, sterile parenteral solution, or liquid spray.
  • the pharmaceutical product comprises a tablet.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • the pharmaceutical composition or pharmaceutical product is a sterile, parenteral solution.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compositions As the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • the pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, preferably a tablet, of at least about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, about 2500, about 2600, about 2700, about 2800, about 2900, about 3000, about 3100, about 3200, about 3300, about 3400, or about 3500 pg.
  • the pharmaceutical composition comprises about
  • the pharmaceutical composition comprises about 200 to about 1600 pg of selexipag. In yet other embodiments, the pharmaceutical composition comprises about 200 pg of selexipag. In still further embodiments, the pharmaceutical composition comprises about 400 pg of selexipag. In other embodiments, the pharmaceutical composition comprises about 800 pg of selexipag. In further embodiments, the pharmaceutical composition comprises about 1000 pg of selexipag. In still other embodiments, the pharmaceutical composition comprises about 1200 pg of selexipag. In yet further embodiments, the pharmaceutical composition comprises about 1400 pg of selexipag. In other embodiments, the pharmaceutical composition comprises about 1600 pg of selexipag.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed.
  • the pharmaceutical compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the principal active ingredient e.g., selexipag
  • a pharmaceutical carrier e.g., a pharmaceutical carrier
  • two active ingredients can be formulated together, e.g., in a bi-layer tablet formulation.
  • the active ingredients are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • selexipag may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the active drug component e.g., selexipag
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • selexipag as the active ingredient, may be intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g., oral or parenteral).
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g., oral or parenteral).
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain, the disclosure of which is hereby incorporated by reference.
  • IQR interquartile range
  • PAH pulmonary arterial hypertension
  • CH pulmonary capillary hemangiomatosis
  • PPA prostacyclin pathway agent
  • PVOD pulmonary veno-occlusive disease
  • mPAP mean pulmonary arterial pressure
  • YHA New York Heart Association
  • PCWP pulmonary capillary wedge pressure
  • PVR pulmonary vascular resistance
  • RAP right atrial pressure
  • WHO World Health Organization
  • AE adverse event.
  • Selexipag is supplied as round, film-coated tablets in different strengths: 200, 400, 600, 800, 1000, 1200, 1400, and 1600 pg strength.
  • compositions are given in Table A and Table B.
  • Table A Composition of selexipag film-coated tablets (200-800 pg)
  • “Transitioned patients” were defined as patients who were (i) taking a non-selexipag PPA for >30 days at the time of selexipag initiation who stopped the initial agent ⁇ 7 days before selexipag initiation; or (ii) continued taking the initial, non-selexipag PPA when they initiated selexipag and gradually transitioned off that agent.
  • the maintenance dose was defined as the first dose post-titration maintained for >14 days without change and/or interruption.
  • the patient data collected included (i) demographics, medical history, disease characteristics, and background therapy; (ii) the transition process from non-selexipag PAH treatments to selexipag and from selexipag to non-selexipag PPAs; (iii) the selexipag dosing regimen; (iv) clinical course and outcomes; and (v) adverse events.
  • AEs known to be associated with the selexipag mechanism of action were only reported if they were serious, led to selexipag discontinuation, or reflected an unusual pattern of severity.
  • Table 1 demographics and disease characteristics for the 56 transitioned patients are shown in Table 1; disease severity data are shown in Table 2.
  • Patient demographics were generally similar between patients who transitioned from parenteral, non-selexipag PPAs vs oral/inhaled, non-selexipag PPAs, although patients who transitioned from parenteral, non- selexipag PPAs were younger; had a shorter time from diagnosis to selexipag initiation; and had a shorter time from selexipag initiation to study enrollment.
  • Median 6MWD, FC distribution, and hemodynamic data suggest that patients who transitioned from parenteral PPAs were in better health than those who transitioned from oral/inhaled, non-selexipag PPAs.
  • the median maintenance dose of selexipag in all transitioned patients was 1400 pg BID (IQR: 1000-1600 pg BID), and the median time to reach this dose was 8.1 weeks (IQR: 6.7-8.7 weeks).
  • the median maintenance dose in patients who transitioned from a parenteral, non-selexipag PPA (1600 pg [IQR: 1400-1600 pg]) was higher than that in those who transitioned from an inhaled/oral, non-selexipag PPA (1300 pg [IQR: 1000-1600 pg]).
  • the median time to reach these doses was 8.1 weeks in both groups (IQR: 5.6-8.4 weeks and 7.7-9.0 weeks in the inhaled/oral and parenteral groups, respectively).
  • FC (FIGs. 1 A and IB) was maintained in the majority of transitioned patients. At 6 months, 27% had improved FC, and none had worsened FC. At 12 months, 21% had improved FC, and 10% had worsened FC. Data, however, were available for only 46% of patients at 6 months and 70% of patients at 12 months. FC results were generally similar between patients who had transitioned from an oral/inhaled, non-selexipag PPA or a parenteral, non-selexipag PPA.

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  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne des méthodes de transition d'un patient traité pour une hypertension artérielle pulmonaire avec un agent de la voie de la prostacycline non sélexipag (PPA) à sélexipag.
EP20727613.0A 2019-05-21 2020-05-20 Méthodes de transition vers sélexipag Pending EP3972602A2 (fr)

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US201962850792P 2019-05-21 2019-05-21
PCT/EP2020/064089 WO2020234361A2 (fr) 2019-05-21 2020-05-20 Méthodes de transition vers sélexipag

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